Cell membranes in general - the erythrocyte membrane in particular - have the very important properties of being both flexible and durable, enabling large, often complex cell distortion without membrane damage. Indeed, the erythrocyte's ability to rapidly - and repetitively - recover its original shape after squeezing through a small capillary vividly demonstrates the intrinsic elasticity and strength of this cell's membrane. Such properties arise in large part from an organized, deformable network of highly conserved cytoskeletal proteins: alpha- and beta- spectrin form long, seemingly flexible crosslinks between short, stiff actin filaments. A compliant, triangulated latticework results. Additional proteins impart further stability to skeletal interactions while linkage of the network to the overlying plasma membrane involves still more membrane proteins. Defects or deficiencies in these proteins lead to hemolytic anemias, of varying severity, but even for normal red cells major unanswered questions persist as to how the components of the erythrocyte membrane skeleton are organized and how this organization changes during deformation. Because the red cell's protein and lipid constituents are ubiquitous among eukaryotic cells, answers to such questions of organization are also very relevant to a host of other structural molecule diseases. Using fluorescence labeling and microscopy to visualize deformation, we began several years ago to quantitatively elucidate the membrane component reorganization that occurs in cell deformation. Complementary, theoretical studies employing very large scale computer simulation have begun to make detailed molecular connections between a thermodynamic structure and observed mechanics. Pursuing these efforts further, we propose to directly measure red cell membrane network stretching, actin filament orientation before/after deformation, and, via thermal fluctutations, elucidate molecular-scale variations and anisotropies within a network under deformation. The study of selected membrane perturbations and pathologies will help reveal the molecular contributions to the mechanics, and, importantly, the mechanical basis of disease. Theoretical work extending to the molecular scale will guide not only the micromanipulation and cell experiments, but will also motivate direct molecular mechanics experiments by Atomic Force Microscopy on engineered spectrin constructs and its complexes.